1. Field of the Invention
This invention is related to 4-substituted piperidine analogs, including hydroxypiperidine and tetrahydropyridine analogs. The analogs are selectively active as antagonists of N-methyl-D-aspartate (NMDA) receptor subtypes. The invention is also directed to the use of 4-substituted piperidine analogs as neuroprotective agents for treating conditions such as stroke, cerebral ischemia, central nervous system trauma, hypoglycemia, anxiety, psychosis, glaucoma, CMV retinitis, urinary incontinence, aminoglycoside antibiotics-induced hearing loss, convulsions, migraine headache, chronic pain, opioid tolerance or withdrawal, or neuro-degenerative disorders such as lathyrism, Alzheimer's Disease, Parkinsonism and Huntington's Disease.
2. Related Background Art
Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this degeneration is in part mediated by the excitotoxic actions of the excitatory amino acids (EAA) glutamate and aspartate at the N-methyl-D-Aspartate (NMDA) receptor. This excitotoxic action is considered responsible for the loss of neurons in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as thromboembolic or hemorrhagic stroke, cerebral vasospasms, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery and cerebral trauma, as well as lathyrism, Alzheimer's Disease, Parkinson's Disease and Huntington's Disease.
Various classes of substituted piperidine analogs are known. For example, EP 0648744 generically discloses phenylalkanol derivatives described by the formula ##STR1## wherein R is hydrogen, hydroxy, or aryl lower alkyloxy; X is hydrogen; Y is hydroxy or hydrogen; or both X and Y taken together are oxygen; Z is aryl lower alkyl; and m is an integer from 1 to 4. The phenylalkanol derivatives of this reference are indicated to be NMDA receptor antagonists that are useful to reduce toxic injury to central neurons and may be used to treat ischemia, stroke or hypoxia. This reference does not disclose or suggest the 4-substituted piperidine analogs of this invention or their use as selective NMDA receptor subtype antagonists.
Other piperidine derivatives having aryl alkanol functionality are disclosed by PCT International Publication No. WO 93/11107 (for treating hypoxia and ischaemia), International Publication No. WO 94/10166 (for treating stroke, addiction, pain, epilepsy, psychosis, traumatic brain injury and CNS degenerative diseases), EP 0398578 (for treating stroke or CNS degenerative diseases, Alzheimer's disease, Huntington's disease and Parkinson's disease) and PCT International Publication No. WO 93/02052 (for treating stroke, traumatic injury to the brain and spinal cord, and neuronal degenerative diseases). Similar to EP 0648744, each of these references requires a piperidine derivative having an alkyl hydroxy or keto group alpha to the aryl group of the N-1 substituent. The 4-substituted piperidine analogs of this invention differ in kind from the piperidine derivatives of these references.
EP 0445701 generically discloses tetrahydropyridine a derivatives described by the formula ##STR2## wherein Ar is phenyl or thienyl which may have identically or differently one or two substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, substituted or unsubstituted phenyl, trifluoromethyl and hydroxy; n is an integer of from 2 to 6; R is hydroxy or a group of the formula: ##STR3## wherein R.sup.1 is hydrogen or lower alkyl; R.sup.2 and R.sup.3 each is hydrogen or lower alkyl or taken together with the adjacent nitrogen atom may form a 5- or 6-membered heterocyclic group, which may be condensed with a benzene ring, where the heterocyclic group may identically or differently have 1 to 3 substituents selected from the group consisting of lower alkyl, halogen, oxo, pyrimidine, and substituted or unsubstituted phenyl; R.sup.4 is NH, O, or a single bond; X.sup.1 and X.sup.2 each is hydrogen, lower alkyl, halogen, or hydroxy; p and q each is an integer of 0 or 1, except that p is 0 when q is 1. These tetrahydropyridines are said to have high affinity and specificity to .sigma. receptors and thus may be effective for treating depression, mania and acute and chronic schizophrenia, and cerebral ischemic disease. There is no disclosure or suggestion of NMDA receptor subtype selectivity.
FR 2681319 discloses 1-(phenoxy-alkyl)piperidine derivatives represented generically by the formula ##STR4## wherein R.sub.1 and R.sub.2 are independently selected from hydrogen, halogen, methoxy or trifluoromethyl, n is 3 or 4 and Y is --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --OCH.sub.2 -- or --CH.sub.2 O--. The reference indicates that these piperidine derivatives are useful for treating cerebral disorders, dementia and other neurodegenerative disorders. The 4-substituted piperidine analogs of this invention or their use as selective NMDA receptor subtype antagonists is not disclosed or suggested.
PCT International Publication No. WO 94/18172 generically discloses imidazolybenzene compounds. represented by the formula ##STR5## wherein R.sup.1, R.sup.2 and R.sup.3 are independently selected from hydrogen, halogen, nitro, cyano, amino, alkyl, acyl, phenyl or alkoxy; R.sup.4 is hydrogen, alkyl or cycloalkyl; Z is --CH.sub.2 --, --CH(OH)-- or --CO--; the ring (a) is piperidyl or 1-piperazinyl; A is hydrogen, hydroxy or alkyl; and B is cycloaklyl, cycloalkylalkyl, acyl, aryl, aralkyl, heteroaryl or heteroarylalkyl. The imidazolylbenzene compound is said to be useful as an NMDA antagonist and cranial nerve cell death inhibitor. However, their is no disclosure of NMDA subtype receptor selectivity.
PCT International Publication Number WO 92/02502 generically discloses N-hydrocarbyl 4-substituted piperidines described by the formula: ##STR6## in which R is C.sub.1-8 alkyl (phenyl)p, C.sub.2-8 alkenyl (phenyl)p, C.sub.2-8 alkynyl (phenyl)p, C.sub.3-8 cycloalkyl;
p is 0 to 2; PA1 n is 0 to 6; PA1 A is a bond, oxygen, sulphur or NR.sup.1 ; PA1 R.sup.1 is hydrogen, C.sub.1-8 alkyl or phenylC.sub.1-4 alkyl; PA1 m is 0 to 3; and PA1 Ar is aryl or heteroaryl, each of which may be optionally substituted; and salts thereof. This reference exemplifies 4-aryloxyalkyl piperidines. The substituted piperidines are said to be calcium channel blockers expected to be useful in the treatment of anoxia, ischemia including stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative disorders and drug addiction. The reference does not disclose or suggest the particular 4-substituted piperidine analogs of this invention or their use as selective NMDA receptor subtype antagonists for the treatment of disorders responsive thereto. PA1 R is C.sub.1-8 alkyl(phenyl)p, C.sub.2-8 alkenyl(phenyl)p, C.sub.2-8 alkynyl(phenyl)p, C.sub.3-8 cycloalkyl or C.sub.1-8 alkylC.sub.3-8 cycloalkyl, or R may also represent hydrogen when k is 2; p is 0 to 2 PA1 n is 0 to 6; PA1 m is 0 to 6; and PA1 A is a bond, --CH.dbd.CH--, --C.tbd.C--, oxygen, sulphur or NR.sup.1 ; PA1 R.sup.1 is hydrogen, C.sub.1-8 alkyl or phenylC.sub.1-4 alkyl; and PA1 Ar is aryl or heteroaryl, each of which may be optionally substituted; provided that: when W is a bond the side chain is a to the ring nitrogen atom; when W is CH.sub.2, k is zero, the side chain is at the 3- or 4-position of the piperidine ring and A is a bond, oxygen, sulphur or NR.sup.1 then Ar is aryl substituted by phenoxy or substituted phenoxy or is a tricyclic heteroaryl group as hereinafter defined; and when W is CH.sub.2 and k is 2 the side chain --(CH.sub.2).sub.n A(CH.sub.2).sub.m Ar is not .alpha. to the nitrogen atom. This reference exemplifies mostly 2 and 3 substituted piperidines. In addition, the particular group of 3 and 4 substituted piperidines described by the reference requires A to be --CH.dbd.CH-- or --C.tbd.C--. This reference does not disclose or suggest the 4-substituted piperidine analogs of this invention. Moreover, there is no suggestion of employing 4-substituted piperidine analogs as selective NMDA receptor subtype antagonists. PA1 A is hydrogen, ##STR9## m is zero to six inclusive; ##STR10## d and n are selected from zero or one and the dotted lines represent double bonds which may form consistent with the valence of carbon; PA1 --NO.sub.2, --O--R.sup.1, ##STR14## --N(R.sup.1).sub.2, --C(O)OR.sup.1, SO.sub.2 R.sup.2, --SR.sup.2, --S(O)R.sup.2, ##STR15## B is selected from ##STR16## z is one or zero with the proviso that z cannot be zero at the same time n is zero when one of the following occurs at the same time that D is phenyl or substituted phenyl: (A).sub.d is hydrogen, (A).sub.d is cyano, (A).sub.d is aminocarbonyl, or a double bond forms between the .alpha. carbon and a carbon of the central heterocyclic amine-ring; R.sup.1 is selected from hydrogen, loweralkyl, phenyl and phenylloweralkyl; R.sup.2 is selected from loweralkyl, phenyl and phenylloweralkyl; M is a pharmaceutically acceptable metal ion and the pharmaceutically acceptable salts thereof, including acid addition salts, quaternary salts, and hydrates and alcoholates thereof. This reference discloses that such compounds may be useful as coronary vasodilators, antihypertensives, antiarrhythmic, antiallergy, antihistamic and antisecretory agents. There is no suggestion or disclosure of the 4-substituted piperidines of this invention or their use as selective NMDA receptor subtype antagonists. PA1 Z is O, S, SO and SO.sub.2 ; PA1 X is (CH.sub.2).sub.m CR.sub.2 R.sub.3 --(CH.sub.2).sub.p and (CH.sub.2).sub.m --CHR.sub.2 --(CH.sub.2).sub.g --CHR.sub.3 (CH.sub.2).sub.p ; PA1 m, p and g is 0-3; PA1 R.sub.2 and R.sub.3 is H, OH 1-4C alkyl or 1-4C alkoxy; PA1 B is CHR.sub.4 or NR.sub.4 ; PA1 R.sub.4 is H, 1-6C alkyl, or ph, Benzyl, benzoyl, .alpha.-hydroxybenzyl or pyridine. PA1 X denotes a group of formula including --(CH.sub.2).sub.n --, --O(CH.sub.2).sub.n --, --S(CH.sub.2).sub.n -- and --NH(CH.sub.2).sub.n --; PA1 n is 1-7; PA1 z is a single or double bond; PA1 X is --(CHR.sup.3).sub.m --, O, S or NR.sup.4, wherein each R.sup.3 is independently hydrogen, hydroxy or a lower alkyl group having 1 to 6 carbon atoms, R.sup.4 is hydrogen or a lower alkyl group having 1 to 6 carbon atoms and m is 0, 1 or 2, provided that when z is a double bond then X is not O or NR.sup.4 ; PA1 R.sup.1 is hydrogen or hydroxy; PA1 each R.sup.2 is independently hydrogen, hydroxy or a lower alkyl group having 1 to 6 carbon atoms; PA1 n is 0, 1, 2, 3 or 4; PA1 Y is O, S, NR.sup.4 or a single bond; and PA1 R.sup.5 is hydrogen or hydroxy when z is a single bond PA1 preferably provided that: (i) R.sup.2 cannot be hydroxy in a position alpha to Ar.sup.2 ; (ii) if X is a single bond, z is a double bond or R.sup.5 is hydroxy and Ar.sup.2 is phenyl then Y cannot be O; (iii) if Y is O, n is 3 or 4, R.sup.2 is exclusively hydrogen, z is a single bond, R.sup.1 and R.sup.5 are hydrogen and Ar.sub.2 is phenyl, or halogen, methoxy, or trifluoromethyl substituted phenyl then X cannot be methylene or ethylene; (iv) if X is --(CHR.sup.3).sub.m --, m is 2 and R.sup.3 is exclusively hydrogen then Ar.sup.1 cannot be imidazolyl substituted; (v) if Y is O, n is 2, 3 or 4, R.sup.2 is hydrogen or hydroxy, z is a single bond, R.sup.1 and R.sup.5 are hydrogen, and Ar.sup.2 is phenyl, or NO.sub.2, CN, 1-imidazoyl, or 1,2,4-triazol-1-yl substituted phenyl then X cannot be methylene, hydroxymethylene, or O; (vi) if Y is O or S, R.sup.1 and R.sup.5 are hydrogen and R.sup.2 is hydroxy then X is not methylene or a single bond; or (vii) if Y is a single bond, R.sup.2 is exclusively hydrogen and Ar.sup.2 is phenyl, then either R.sup.1 or R.sup.5 must be hydroxy. PA1 z is a single or double bond; PA1 X is --(CHR.sup.3).sub.m --, O, S or NR.sup.4, wherein each R.sup.3 is independently hydrogen, hydroxy or a lower alkyl group having 1 to 6 carbon atoms, R.sup.4 is hydrogen or a lower alkyl group having 1 to 6 carbon atoms and m is 0, 1 or 2, provided that when z is a double bond then X is not O or NR.sup.4 ; PA1 R.sup.1 is hydrogen or hydroxy; PA1 each R.sup.2 is independently hydrogen, hydroxy or a lower alkyl group having 1 to 6 carbon atoms; PA1 n is 0, 1, 2, 3 or 4; PA1 Y is O, S, NR.sup.4 or is a single bond; and PA1 R.sup.5 is hydrogen or hydroxy when z is a single bond.
PCT International Publication Number WO 93/15052 generically describes compounds that are said to be calcium channel antagonists broadly represented by the formula: ##STR7## and the salts thereof, wherein W is --CH.sub.2 --, a bond, O or S; k is 0, or when W represents --CH.sub.2 -- k may also be 2, in which case the dotted lines represent single bonds;
European Patent Application No. 235,463 generically discloses calcium antagonists represented by the formula ##STR8## wherein; p is zero, one or two;
Ar, D and R are selected from the group consisting of ##STR11## and in addition, R may have the values: ##STR12## cycloalkyl or loweralkyl, and D may have additionally the values: ##STR13## Ar(CH.sub.2).sub. 1-4 X, Y and Z are selected from the group consisting of hydrogen, lower alkyl, halogen,
U.S. Pat. No. 5,202,346 generically discloses a compound represented by the formula ##STR17## wherein R.sup.1 is alkylsulfonamido of 1 to 6 carbon atoms, arylsulfonamide of 6 to 10 carbon atoms, --NO.sub.2, --CN, 1-imidazolyl or 1,2,4-triazol-1-yl; Y is ##STR18## --CH.sub.2 --, --O--, --S--, or --SO.sub.2 --; R.sup.2 is hydrogen when n is 0, otherwise it is hydrogen or --OH; n is one of the integers 0, 1, 2, 3, 4, 5 or 6; A is ##STR19## where R.sup.3 is alkylsulfonamide of 1 to 6 carbon atoms, arylsulfonamido of 6 to 10 carbon atoms, --NO.sub.2, --CN, 1-imidazoyl or 1,2,4-triazol-1-yl. These compounds are said to be Class III antiarrhythmic agents. JP 61-115068 discloses 4-benzylpiperidinylpropoxyaniline derivatives, such as 2-(3-(4-benzyl-1-piperidinyl)propoxy)aniline, also said to have antiarrhythmic, as well as local anesthetic action. No mention is made of NMDA antagonists, let alone selective subtype receptor antagonists.
U.S. Pat. No. 5,036,077 generically discloses piperidine derivatives described by the formula: ##STR20## wherein Ar represents a phenyl group substituted by R.sub.2, R.sub.3 and R.sub.4 or a naphth-1-yl or naphth-2-yl group, substituted or unsubstituted by 1 or 2 halogen atoms; X represents an oxygen atom or sulfur atom; R.sub.1 represents H or a halogen atom; R.sub.2 represents a halogen atom, a trifluoromethyl group, a phenyl group which is unsubstituted or substituted by 1 to 3 halogen atoms, a phenoxy group which is unsubstituted or substituted by 1 to 3 halogen atoms, or a C.sub.1 -C.sub.4 alkyl group and the benzyl group substitutes the piperidine radical in the 2, 3 or 4 position. The piperidines are said to be useful as antimicrobial agents, but there is no disclosure or suggestion of treating disorders responsive to selective NMDA receptor subtype antagonists.
European patent application No. 649838 generically disclosed cyclized amines described by the formula: ##STR21## wherein the nitrogen heterocycles can be 3-8 member rings and substituted in the 2-4 positions. Ar and Ar' are opt. mono or disubstituted phenyl. The compounds are said to be useful to treat arrhythmia and tachycardia. But there is no disclosure or suggestion of treating disorders responsive to selective NMDA receptor subtype antagonists.
DE patent application No. 4410822 generically disclosed cyclized amines described by the formula: ##STR22## in which R.sub.1 is Ph, pyridine and other heterocycles;
The compounds are said to be used in the treatment and therapy of diseases which are relieved by changing the function of the AMPA receptor complex. But there is no disclosure or suggestion of treating disorders responsive to selective NMDA receptor subtype antagonists.
U.S. Pat. No. 4,942,169 generically disclosed substituted piperidines described by the formula: ##STR23## in which R.sub.1 is substituted or unsusbstituted Ph or heterocycles;
the ring A denotes a group of the formula ##STR24## R.sub.2 denotes a H, a lower alkyl group, a substituted or unsubstituted benzyl, benzoyl, pyridyl, 2-hydroxyethyl and pyridylmethyl.
The compounds are said to have antiacetylcholinesterase activities. But there is no disclosure or suggestion of treating disorders responsive to selective NMDA receptor subtype antagonists.
U.S. Pat. No. 5,169,855 generically discloses disubstituted piperidine ether derivatives for use as antipsychotic agents selective for sigma receptors. Similarly, PCT International Publication No. WO 92/18127 and PCT International Publication No. WO 91/06297 generically disclose N-phthalimidoalkyl piperidines which are useful as antipsychotic agents and which are selective for sigma receptors. However, the 4-substituted piperidine analogs of this invention are not disclosed by these references and there is no mention of NMDA receptor activity.
Numerous references have disclosed additional piperidine derivatives substituted at the 4 and 3 position for use in a variety of treatments. Such references include, for example, U.S. Pat. No. 3,255,196 (3 and 4-substituted piperidines that are active antitussives and possess analgesic, antiemetic and local anaesthetic properties); PCT International Publication No. WO 88/02365 (3 and 4-substituted piperidines that may be useful for treatment of mental disorders accompanying cerebrovascular disease); BE 860701 (4-substituted piperidines for use as vasodilators and .beta.-adrenergic inhibitors); JP 04-312572 (4-substituted piperidines, such as 4-(4-(N,N-dimethylaminocarbonyl)phenylmethyl)piperidine, for treatment of cerebral ischemia); JP 61-227565 (4 substituted piperidine derivatives for treating diseases requiring the isolation of serotonin); EP 0449186 (4-substituted N-aralkyl piperidines which are selective sigma receptor antagonists for treating physiological or drug induced psychosis or dyskinesia); and DE 2939292 (4-substituted piperidines for use as antiallergenic and antiinflammatory agents). None of these references disclose or suggest the 4-substituted piperidine analogs of the present invention or their use as selective NMDA receptor subtype antagonists.
Excitatory amino acid receptor antagonists that block NMDA receptors are recognized for usefulness in the treatment of disorders. NMDA receptors are intimately involved in the phenomenon of excitotoxicity, which may be a critical determinant of outcome of several neurological disorders. Disorders known to be responsive to blockade of the NMDA receptor include acute cerebral ischemia (stroke or cerebral trauma, for example), muscular spasm, convulsive disorders, neuropathic pain and anxiety, and may be a significant causal factor in chronic neurodegenerative disorders such as Parkinson's disease [T. Klockgether, L. Turski, Ann. Neurol. 34, 585-593 (1993)], human immunodeficiency virus (HIV) related neuronal injury, amyotrophic lateral sclerosis (ALS), Alzheimer's disease [P. T. Francis, N. R. Sims, A. W. Procter, D. M. Bowen, J. Neurochem. 60 (5), 1589-1604 (1993)] and Huntington's disease. [See S. Lipton, TINS 16 (12), 527-532 (1993); S. A. Lipton, P. A. Rosenberg, New Eng. J. Med. 330 (9), 613-622 (1994); and C. F. Bigge, Biochem. Pharmacol. 45, 1547-1561 (1993) and references cited therein.]. NMDA receptor antagonists may also be used to prevent tolerance to opiate analgesia or to help control withdrawal symptoms from addictive drugs (Eur. Pat. Appl. 488,959A).
Expression cloning of the first NMDA receptor subunit, NMDAR1 (NR1) in Nakanishi's lab in 1991 provided an initial view of the molecular structure of the NMDA receptor [Nature 354, 31-37 (1991)]. There are several other structurally related subunits (NMDAR2A through NMDAR2D) that join NR1 in heteromeric assemblies to form the functional ion channel complex of the receptor [Annu. Rev. Neurosci. 17, 31-108 (1994)]. The molecular heterogeneity of NMDA receptors implies a future potential for agents with subtype selective pharmacology.
Many of the properties of native NMDA receptors are seen in recombinant homomeric NR1 receptors. These properties are altered by the NR2 subunits. Recombinant NMDA receptors expressed in Xenopus oocytes have been studied by voltage-clamp recording, as has developmental and regional expression of the mRNAs encoding NMDA receptor subunits. Electrophysiological assays were utilized to characterize the actions of compounds at NMDA receptors expressed in Xenopus oocytes. The compounds were assayed at four subunit combinations of cloned rat NMDA receptors, corresponding to three putative NMDA receptor subtypes [Moriyoshi, et al. Nature 1991, 354, 31-37; Monyer et al, Science 1992, 256, 1217-1221; Kutsuwada et al, Nature 1992, 358, 36-41; Sugihara et al, Biochem. Biophys Res. Commun. 1992, 185, 826-832].
An object of this invention is to provide novel 4-substituted piperidine analogs which function as subtype-selective NMDA receptor antagonists.
A further object of this invention is to provide a pharmaceutical composition containing an effective amount of the 4-substituted piperidine analogs to treat cerebrovascular disorders responsive to the selective blockade of NMDA receptor subtypes.
Another object of this invention is to provide a method of treating disorders responsive to the subtype-selective NMDA receptor antagonists in an animal by administering a pharmaceutically effective amount of 4-substituted piperidine analogs.